Endoplasmic reticulum glucosidase II is inhibited by its end products

Eran Bosis, Esther Nachliel, Tamar Cohen, Yoichi Takeda, Yukishige Ito, Shoshana Bar-Nun*, Menachem Gutman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The calnexin/calreticulin cycle is a quality control system responsible for promoting the folding of newly synthesized glycoproteins entering the endoplasmic reticulum (ER). The association of calnexin and calreticulin with the glycoproteins is regulated by ER glucosidase II, which hydrolyzes Glc 2ManXGlcNAc2 glycans to Glc1Man XGlcNAc2 and further to Glc0Man XGlcNAc2 (X represents any number between 5 and 9). To gain new insights into the reaction mechanism of glucosidase II, we developed a kinetic model that describes the interactions between glucosidase II, calnexin/calreticulin, and the glycans. Our model accurately reconstructed the hydrolysis of glycans with nine mannose residues and glycans with seven mannose residues, as measured by Totani et al. [Totani, K., Ihara, Y., Matsuo, I., and Ito, Y. (2006) J. Biol. Chem. 281, 31502-31508]. Intriguingly, our model predicted that glucosidase II was inhibited by its nonglucosylated end products, where the inhibitory effect of Glc0Man7GlcNAc2 was much stronger than that of Glc0Man9GlcNAc 2. These predictions were confirmed experimentally. Moreover, our model suggested that glycans with a different number of mannose residues can be equivalent substrates of glucosidase II, in contrast to what had been previously thought. We discuss the possibility that nonglucosylated glycans, existing in the ER, might regulate the entry of newly synthesized glycoproteins into the calnexin/calreticulin cycle. Our model also shows that glucosidase II does not interact with monoglucosylated glycans while they are bound to calnexin or calreticulin.

Original languageEnglish
Pages (from-to)10970-10980
Number of pages11
Issue number41
StatePublished - 14 Oct 2008


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